Lyophilizationn.pdf

Lyophilization or freeze drying is a process in which water is removed from a product after it is frozen and placed under a vacuum, allowing the ice to change directly from solid to vapor without passing through a liquid phase. The process consists of three separate, unique, and interdependent processes; freezing, primary drying (sublimation), and secondary drying (desorption).

The advantages of lyophilization include:

Ease of processing a liquid, which simplifies aseptic handling

Enhanced stability of a dry powder

Removal of water without excessive heating of the product

Enhanced product stability in a dry state

Rapid and easy dissolution of reconstituted product

Disadvantages of lyophilization include:

Increased handling and processing time

Need for sterile diluent upon reconstitution

Cost and complexity of equipment

The lyophilization process generally includes the following steps:

Dissolving the drug and excipients in a suitable solvent, generally water for injection (WFI).
Sterilizing the bulk solution by passing it through a 0.22 micron bacteria-retentive filter.
Filling into individual sterile containers and partially stoppering the containers under aseptic conditions.
Transporting the partially stoppered containers to the lyophilizer and loading into the chamber under aseptic conditions.
Freezing the solution by placing the partially stoppered containers on cooled shelves in a freeze-drying chamber or pre-freezing in another chamber.
Applying a vacuum to the chamber and heating the shelves in order to evaporate the water from the frozen state.
Complete stoppering of the vials usually by hydraulic or screw rod stoppering mechanisms installed in the lyophilizers.
There are many new parenteral products, including anti-infectives, biotechnology derived products, and in-vitro diagnostics which are manufactured as lyophilized products. Additionally, inspections have disclosed potency, sterility and stability problems associated with the manufacture and control of lyophilized products. In order to provide guidance and information to investigators, some industry procedures and deficiencies associated with lyophilized products are identified in this Inspection Guide.

It is recognized that there is complex technology associated with the manufacture and control of a lyophilized pharmaceutical dosage form. Some of the important aspects of these operations include: the formulation of solutions; filling of vials and validation of the filling operation; sterilization and engineering aspects of the lyophilizer; scale-up and validation of the lyophilization cycle; and testing of the end product. This discussion will address some of the problems associated with the manufacture and control of a lyophilized dosage form.

1. INTRODUCTION :-
• Lyophilization is also known as Freeze Drying or Cryodesiccation is a dehydration
process typically used to preserve a perishable material or made the material more
convenient for transport.
• It is a special form of drying that removes all moistures and tends to have less effect on
a food’s taste than normal dehydration process.
• In this process , food is frozen and placed in a strong vacuum . The water in the food
sublimates , it turns straight from ice into vapour.
• Process was first applied to the food products after the second world war.
• Coffee was first freeze dried food product to be produced.


DEFINITION :-
A stabilizing process in which a substance is first frozen and then the quantity of the solvent is
reduced , first by sublimation (primary drying stage) and then desorption (secondary drying
stage) to values that will no longer support biological activity or chemical reactions.


PRINCIPLE :-
• Lyophilization is carried out using a simple principle of physics sublimation. Sublimation
is the transition of a substance from the solid to the vapour state , without first passing
through an intermediate liquid phase.
• Lyophilization is performed at temperature and pressure conditions below the triple
point , to enable sublimation of ice.
• Triple point of water is a point where , water exists in all the three phases, the solid , the
liquid and the gas. This point is achieved at the temperature of 0.01°C and the pressure
of 0.00603 atm.
• The entire process is performed at low temperature and pressure by applying vacuum ,
hence is suited for drying of thermolabile compounds.
• So , when the process is performed below these conditions the solid ice is directly
converted into the gaseous form without converting into the liquid.
• So , in this technique thr liquid is frozen to solid and then is converted to gas , to remove
all the moisture or solvent present in it.

2. TYPES :-
The types of lyophilizer are classified as –
1. On the basis of their size.
2. On the basis of their capacity.
1. On the basis of size :- Depending upon the size they can be classified as –
A Typical Manifold Dryer
B Shelf Freeze Dryer
C Combination Lab Freeze Dryer


2. On the basis of capacity :- Depending upon the capacity they can be classified as –
A Bench Top Freeze Dryer
B Pivot Freeze Dryer
C Production Freeze Dryer

COMPONENTS OF LYOPHILIZER :-
The main components of lyophilizer are –
• Chamber
• Shelves
• Refrigerator System
• Condenser
• Vacuum Pump

3. 1. Chamber :- A chamber is tight insulated box pf stainless steel consisting of shelves.
2. Shelves :- Shelves on which products are kept and acts as a heat exchanger.
3. Refrigerator System :- A refrigerator system , which has a compressor which cools the
condenser.
4. Condenser :- Condenser is a form of coils or plates for trapping solvent vapours.
5. Vacuum Pump :- A vacuum pump is there for lowering the temperature.


PROCESS OF LYOPHILIZATION :-
The process of lyophilization involves following steps –
1. Pre treatment
2. Freezing Stage
3. Primary Drying Stage
4. Secondary Drying Stage
5. Packing

4. 1. Pre Treatment :-
• This stage include all the methods of treating the product prior to freezing
• Such as – concentrating the product to make it stable such that the minimum amount of
the solvent is present from the beginning only.
• Formulation revision i.e addition of cryoprotectants.
• Decreasing the high vapour pressure solvent.
• Increasing the surface area.

2. Freezing Stage or Freeze Drying Stage :
• In this stage the product is frozen to ice.
• The product is frozen below it’s euthentic temperature.
• Low temperature and pressure is maintained.
• Decreasing the shelf temperature to -50°C.
• In the laboratory , it is done by placing the product in the freeze dryer flask , which is
rotated in the shell freezer bath , which is cooled by dry ice , methanol or mechanical
refrigeration etc.

3. Primary Drying [ Sublimation ]:
▪ In the stage the temperature and pressure are kept below the triple point of water .
▪ That is the temperature.0.0098°C and pressure 4.58 mmHg
▪ Heat is introduced from the shelf to the product under the granted control by electrical
resistance cells or circulating silicon.
▪ Rate of sublimation of ice depends upon difference in V.P of product ad V.P of
condenser
▪ 95-98% of Water is removed , and process takes 20-24 hours .

4. Secondary Drying [ Desorption ]:
▪ It is also known as Isothermal Desorption
▪ Which removes the remaining solvent form the product .
▪ It removes the bound water .
▪ It is continued at same pressure but the temperature is increased around +10-40°C
▪ It takes about 10-20hrs.

5. 5. Packing :

▪ After drying the vaccum is replaced by filtered air or nitrogen to establish atmospheric
pressure .
▪ Ampoules are sealed by either tip sealing or clousers and aluminium caps .
▪ Vials and bottles are sealed with rubber clousers and alluminium caps.


APPLICATIONS OF LYOPHILIZATION :-
Following are the applications of lyophilization –
1. Pharmaceutical Industry and Biotechnology :-
• Pharmaceutical companies often use freeze drying to increase the shelf life of products ,
such as vaccines and other injectable.
• By removing the water from the material and sealing the material in a vial , the material
can be easily stored , shipped and later reconstituted to its original form for injection.
2. Food Industry :-
• Freeze – drying is used to preserve food and make it very light weight.
• The process has been popularized in the forms of freeze dried icecream ; an example of
astronaut food.
• Instant coffee powder is prepared.
• To produce essences or flavouring agents.
• Culinary herbs are preserved.
• Freeze dried fruits are produced.
3. Technological Industries :-
• In chemical synthesis , products are often lyophilized to make them more stable , or
easier to dissolve in water for subsequent use.
• It is also capable of concentrating substances with low molecular weights that are two
small to be removed by a filtration membrane.
4. Other uses :-
• Freeze-drying is used for flora and fauna preservation.
• It is also used for recovery of water- damaged books and documents.

6. ADVANTAGES OF LYOPHILIZATION :-
Following are the advantages of lyophilization –
• Minimum damage to heat labile material.
• Removal of water at low temperature.
• Compatible with aseptic operations.
• Sterility can be maintained.
• Reconstitution is easy.
• Increasing shelf life of the product.
• Doesnot shrink the samples.
• Reduces weight and volume of samples ; ideal for shipping .
• Samples can be stored at room temperature indefinitely.

DISADVANTAGES OF LYOPHILIZATION :-
Following are the disadvantages of lyophilization –
• High capital cost of equipment.
• High energy cost.
• Time consuming process ( Typically 4-10 hrs per drying cycle ).
• Possible damage to products due to change in pH and tonicity.
• Many biological molecules are damaged by the stress associated with freezing.
• The open porous structure of the food may allow oxygen to enter and cause oxidative
degradation of lipids (packing in inert gas necessary).